The major goal of this R21 application is to develop methods for 3D orthogonal compound ultrasound (OCU) for two potential applications: (a) interstitial prostate therapy guidance and verification; (b) breast cancer diagnosis. OCU is a technique that emerged in our recent studies on ultrasound-based seed detection. Preliminary data indicate that OCU provides increased signal-to-noise and contrast-to-noise ratios, and reduces shadowing artifacts and speckle noise. Current standard techniques of ultrasound tissue typing, image guidance and therapy verification are based on 2D ultrasound imaging from a single look angle, which is known to suffer from noise and artifacts. Although 3D ultrasound is being introduced in some applications, the 3D image cube is still constructed from multiple single plane images. Automatic tracking of the prostate target and localization of implanted seeds are not consistently achievable in the operating room. Breast tissue type discrimination between benign vs. malignant changes is also uncertain, resulting in low specificity and therefore significant percent of unnecessary biopsies in clinical applications. The 3D orthogonal compound ultrasound (OCU) imaging technique is proposed to overcome these drawbacks. It uses a standard ultrasound probe to acquire two orthogonally spaced 3D image volumes from transverse, longitudinal or rotational scans, which are then reconstructed, registered and combined into a compounded volume. Data collection for OCU in prostate therapy of 18 patients is already underway under an IRB approved protocol. Quantitative studies to determine improvements in target tissue identification and therapy verification are proposed. Data collection for OCU in breast cancer detection and correlation with pathological findings in 50 patients are additionally proposed. The long-term goals are (a) to use OCU imaging as a standard guidance and real-time verification method for prostate cancer diagnosis and intratumoral therapy deliveries; (10) to develop computer-aided tissue typing on OCU for breast cancer diagnosis and screening; and (c) to develop methods for orthogonal compounding of intra-cranial, thyroid and trans-abdominal/pelvic ultrasound.